The vitamin D receptor (VDR) is a ligand-dependant transcriptional regulator that belongs to the nuclear receptor (NR) transcription factor family (1), which controls cell growth and differentiation, homeostasis, development, and several physiological processes. Ligand binding to VDR induces a conformational change in the orientation of the AF-2 core motif allowing the interaction with coactivators that mediate the interaction between the nuclear receptor and the basal transcription machinery (2-4).
The plethora of actions of 1α,25(OH)2D3, the natural ligand of VDR, in various physiological processes suggested wide clinical applications for vitamin D nuclear VDR ligands in treatments of inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological disorder (psoriasis, photoaging), osteodystrophy, osteoporosis, cancers (breast, prostate, colon, leukemia), and autoimmune diseases (multiple sclerosis, type I diabetes) (5-7). However, the calcemic effects induced by 1α,25(OH)2D3 causing hypercalcemia, increasing bone resorption, and soft tissue calcification limit the use of the natural ligand in these clinical applications, and this had led to the development of analogs with reduced side effects.
Some synthetic analogs of 1α,25(OH)2D3 have shown to be superagonists. These analogs are at least 10 times more potent than 1α,25(OH)2D3 in transactivation and present antiproliferative activity several orders of magnitude higher than the 1α,25(OH)2D3 (8-10).
The present invention provides a new class of compounds which are analogs of 1α, 25(OH)2D3. In particular, the invention provides VDR modulators, e.g., agonists or antagonists. Interestingly, the invention also provides superagonists of VDR in vitro test. These analogs are also effective in vivo. It further provides analogs of 1α, 25(OH)2D3 which exhibit low-hypercalcemia effect.